Worker exposure to vanadium-bearing fumes and dusts in industrial settings is known to reduce their resistance to many pulmonary diseases. Pulmonary macrophages are the cells within the lungs that are primarily responsible for maintaining organ sterility as well as initiating immune responses to remove any antigenic challenges. Because the lungs are the major route for delivery of vanadium into the body, the macrophages are likely targets for toxic immunomodulation. Previous in vivo and in vitro studies with pulmonary and other tissue macrophages have demonstrated that various aspects of macrophage activity, including receptor-mediated binding, phagocytosis and intracellular killing of bacteria, cytokine and prostaglandin release, reactive oxygen intermediate generation, and surface Fc-receptor expression, are altered following exposure to vanadium. The goal of this proposal is to delineate a possible unifying underlying mechanism for the observed immunosuppression. In particular, it is hypothesized here that the pulmonary macrophage capacity to produce, bind, and/or process cytokines responsible for the early- and late-stage activation of macrophage (interferons-alpha and -gamma [IFNalpha and IFNgamma) are modified by exposure to vanadium. Three specific aims are proposed to substantiate this: (1) to assess the levels of inducible IFNalpha and IFNgamma by pulmonary macrophage (and other accessory cells) in the intact rat lung following inhalation of vanadium metal in the forms/concentrations encountered under workplace conditions; (2) to determine if the inhaled vanadium alters macrophage IFNalpha/gamma surface receptor expression or IFN binding, the intracellular delivery and subsequent dissociation of the receptor-IFN complex, or the recycling/de novo synthesis of surface IFN receptors; and (3) to relate any changes in these measured parameters to overall changes in macrophage responsiveness to exogenous IFNgamma, i.e., IFNgamma-induced expression of Class II MHC surface antigens and enhanced production of reactive oxygen intermediates. The results from this study will be useful in clarifying the precise mechanisms by which vanadium causes immunosuppression by disturbing crucial macrophage-cytokine interactions in exposed workers.